Investigator Final Reports: A Tool for FDA Inspection Readiness
For Pharmaceuticals and Biotechnology
During the time I was an FDA field investigator I encountered many clinical investigators who were totally unprepared for the FDA inspection. I would receive a "deer gazing into the headlights" response from the PI who obviously didn't remember a thing about the audited study. There is an old saying, "you only get one chance to make a good first impression." Often they would turn to their study coordinator and ask for the answer, joking to me, "They do all the work anyway."
One of the most important parts of an FDA inspection is determining the involvement of the clinical investigator (often referred to as the "PI") and how the study was supervised.
That is absolutely the wrong thing to say to an FDA investigator. A clinical investigator is responsible for administering the study drug "only to subjects under the investigator's personal supervision or under the supervision of a sub-investigator responsible to the investigator."1 One of the most important parts of an FDA inspection is determining the involvement of the clinical investigator (often referred to as the "PI") and how the study was supervised. Preparing a clinical investigator for an FDA inspection is essential for every sponsor of a clinical trial. The sponsor has his own responsibilities, including monitoring the progress of the investigation.2
This isn't always easy. Clinical investigators are usually busy people and a clinical trial may be inspected by FDA years after the conduct of the study. However, there is an overlooked requirement that can be used as a tool to help prepare investigators and their clinical staff for an FDA inspection. The drug and biologic IND regulations require that an investigator submit a final report to the sponsor shortly after the investigator's participation in the study is concluded.3 The medical device IDE regulations have the same type of requirement.4
This is different from the final report required by IRBs. Many times I am asked if the PI can just use the final report submitted to the IRB. The answer is probably, but why? FDA has guidance documents such as their Compliance Program Guidance Manual5 that tell you what an FDA investigator will want to know during an inspection. Why not prepare the answers in advance? If there is a short report with the relevant details prepared at the end of the study, then it can be used to prepare the investigator down the road when FDA comes knocking. When an investigator is well-prepared for an inspection, he is demonstrating his knowledge of the study and making the right first impression on the FDA. This starts the inspection off in the best direction. Here are some basic elements for a final report taken from FDA guidance documents including the CDRH "Device Advice."6
IND or IDE number
Investigation product name
Indications for use
Brief summary of study progress in relation to investigational plan
Number of subjects enrolled, dropped, completed
Amount of investigational product received, used, and the final disposition of unused IP
Brief summary of results and conclusions
Summary of anticipated and unanticipated adverse device effects or adverse drug experiences
Description of any deviations from investigational plan
Reprints of any articles published by the investigator in relation to the study
Finally, there are some important dates that take place. Including these in the final report will keep the PI one step ahead of the FDA investigator's questions:
The dates of IRB approvals (human studies) including initial review of the protocol, all amendments, the informed consent document and all revised informed consent documents
When the Form FDA 1572 or Investigator Agreement (for devices) was signed by the clinical investigator
When the first subject was screened
When the first subject signed the informed consent form
First administration of the test article; and
Last follow-up for any study subject.
This is all information that you would expect a sponsor and a clinical investigator to have for an adequate and well-controlled trial. Keeping on top of this information during the conduct of the study and using it to prepare a final report as required by the regulations will go a long way in preparing for a successful FDA inspection.
References:
21 CFR 312.61
21 CFR 312.56(a)
21 CFR 312.64(c)
21 CFR 812.150(a)(6)
FDA Compliance Program Guidance Manual, CP 7356.811, Clinical Investigators: https://www.fda.gov/ICECI/EnforcementActions/BioresearchMonitoring/ucm133562.htm
FDA Device Advice: https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/
Carl Anderson is a Tacoma, Washington-based regulatory affairs and quality assurance consultant in the field of FDA health product approvals including drugs, biologics, and medical devices. From 1987 to 2005 he worked for the United States Food and Drug Administration. In 1994 he began conducting inspections in the Bioresearch Monitoring program and inspected clinical investigators, institutional review boards, nonclinical laboratories, and sponsors of clinical research.
Anderson's experience also includes postmarketing surveillance of adverse drug experiences and good manufacturing practice of drug products. He was on the FDA's international inspection cadre and has conducted audits and inspections in Canada, Europe, the Middle East, and East Asia. Since leaving FDA he has focused on assisting clinical trial sponsors develop clinical quality assurance systems and preparing sponsors and clinical sites for FDA Bioresearch Monitoring inspections.
Anderson has made frequent public presentations on good clinical practice, quality assurance, and FDA regulations to professional and industry organizations including the Society of Quality Assurance, Drug Information Association, Regulatory Affairs Professional Society, and Association for Clinical Research Professionals. He also conducts training for private industry as well as public agencies such as the Centers for Disease Control and Prevention (CDC) and university extension services.
Anderson may be reached by phone at 253-307-6513 or via email at [email protected]. Read his blog at www.carlanderson.wordpress.com.